Vitamin D analogue-specific recruitment of vitamin D receptor coactivators

Issa, L. L., Leong, G. M., Sutherland, R. L. and Eisman, J. A. (2002) Vitamin D analogue-specific recruitment of vitamin D receptor coactivators. Journal of Bone And Mineral Research, 17 5: 879-890. doi:10.1359/jbmr.2002.17.5.879


Author Issa, L. L.
Leong, G. M.
Sutherland, R. L.
Eisman, J. A.
Title Vitamin D analogue-specific recruitment of vitamin D receptor coactivators
Journal name Journal of Bone And Mineral Research   Check publisher's open access policy
ISSN 0884-0431
Publication date 2002-01-01
Year available 1998
Sub-type Article (original research)
DOI 10.1359/jbmr.2002.17.5.879
Open Access Status Not yet assessed
Volume 17
Issue 5
Start page 879
End page 890
Total pages 12
Place of publication Washington
Publisher Amer Soc Bone & Mineral Res
Language eng
Abstract Synthetic ligands for the vitamin D receptor (VDR) are potential therapeutic agents for metabolic, neoplastic, and autoimmune disorders. Some of these ligands have similar or more potent antiproliferative, yet reduced hypercalcemic actions, than calcitriol. However, the mechanisms for these differential actions have not been clearly defined. We hypothesized that these gene- and tissue-specific effects may relate to ligand-directed selective recruitment of transcriptional coactivators. To identify key elements in ligand structure that facilitate VDR-coactivator interactions, the current studies assessed the ability of the VDR to recruit the coactivators GRIP1 and RAC3 following activation by a series of 20-R- and 20-S (20-epi)-modified analogues. The strength of VDR-coactivator interactions was ligand-specific and did not always correlate with ligand-receptor binding affinity. In general, the 20-epi analogues enhanced these interactions, whereas the 20-R-modified analogues were less effective than calcitriol. The 16-ene,23-yne modification and fluorinated substituents to the side-chain attenuated interaction with coactivators. The enhanced ability of the VDR to recruit GRIP1 following activation by the 20-epi analogues was consistent with potentiation of 20-epi analogue-induced transactivation of the osteocalcin gene promoter by GRIP1. Overall, the structure of the ligand side-chain as well as its orientation seemed to affect the avidity of coactivator binding. These results suggest that selective recruitment of coactivators may contribute to gene- and tissue-specific effects of vitamin D analogues.
Keyword Endocrinology & Metabolism
vitamin D analogues
vitamin D receptor
retinoid X receptor
GRIP1
RAC3
Retinoid-x-receptor
Transcription Factor Iib
Nuclear Receptor
Histone Acetyltransferase
Crystal-structure
Breast-cancer
Rar-gamma
Ligand
Activation
Binding
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status Unknown

Document type: Journal Article
Sub-type: Article (original research)
Collections: Excellence in Research Australia (ERA) - Collection
Institute for Molecular Bioscience - Publications
 
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Created: Thu, 20 Sep 2007, 02:46:28 EST